Exploring the Hepatotoxicity of Drugs through Machine Learning and Network Toxicological Methods

Background: The prediction of the drug-induced liver injury (DILI) of chemicals is still a key issue of the adverse drug reactions (ADRs) that needs to be solved urgently in drug development. The development of a novel method with good predictive capability and strong mechanism interpretation is still a focus topic in exploring the DILI. Objective: With the help of systems biology and network analysis techniques, a class of descriptors that can reflect the influence of drug targets in the pathogenesis of DILI is established. Then a machine learning model with good predictive capability and strong mechanism interpretation is developed between these descriptors and the toxicity of DILI. Methods: After overlapping the DILI disease module and the drug-target network, we developed novel descriptors according to the number of drug genes with different network overlapped distance parameters. The hepatotoxicity of drugs is predicted based on these novel descriptors and the classical molecular descriptors. Then the DILI mechanism interpretations of drugs are carried out with important network topological descriptors in the prediction model. Results: First, we collected targets of drugs and DILI-related genes and developed 5 NT parameters (S, Nds=0, Nds=1, Nds=2, and Nds>2) based on their relationship with a DILI disease module. Then hepatotoxicity predicting models were established between the above NT parameters combined with molecular descriptors and drugs through the machine learning algorithms. We found that the NT parameters had a significant contribution in the model (ACCtraining set=0.71, AUCtraining set=0.76; ACCexternal set=0.79, AUCexternal set=0.83) developed by these descriptors within the applicability domain, especially for Nds=2, and Nds>2. Then, the DILI mechanism of acetaminophen (APAP) and gefitinib are explored based on their risk genes related to ds=2. There are 26 DILI risk genes in the regulation of cell death regulated with two steps by 5 APAP targets, and gefitinib regulated risk gene of CLDN1, EIF2B4, and AMIGO1 with two steps led to DILI which fell in the biological process of response to oxygen-containing compound, indicating that different drugs possibly induced liver injury through regulating different biological functions. Conclusion: A novel method based on network strategies and machine learning algorithms successfully explored the DILI of drugs. The NT parameters had shown advantages in illustrating the DILI mechanism of chemicals according to the relationships between the drug targets and the DILI risk genes in the human interactome. It can provide a novel candidate of molecular descriptors for the predictions of other ADRs or even of the predictions of ADME/T activity.